This is a proposal to investigate the functional significance of the heme-heme oxygenase-carbon monoxide (CO) system in the progression from reversible shock to circulatory collapse after hemorrhagic loss. An inducible isoform of heme oxygenase (HO) is a well established "heat shock protein" (HSP32, HO-1) which catalyzes the conversion of heme to biliverdin, free iron and CO. While a number of studies have focused on the potential roles for HO-1 in the regulation of P-450, and for the antioxidative biliverdin product, recent work suggests that the HO-derived CO can suppress sympathetic discharge, promote relaxation of vascular smooth muscle, and inhibit nitric oxide synthase in the vascular endothelium. In the vasculature, endogenously-formed CO acts 1) as an agent which promotes relaxation of vascular smooth muscle and 2) to inhibits NO synthesis and promote an offsetting constrictive element. Since CO is generated by HO, a shock protein, experimental forms of shock can be accompanied by induction of HO and enhanced CO formation. Accordingly, we reason that this induction of HO and the consequent formation of CO may interfere with flow induced dilation to compromised tissue perfusion, and continued over expression could facilitate relaxation of vascular smooth muscle and precipitate circulatory collapse. My hypothesis is that HO-mediated formation of CO is enhanced following hemorrhagic accident to impede microcirculatory flows, and that excessive expression leads to circulatory collapse by reducing vascular smooth muscle tone. Furthermore, I speculate that the pharmacologic inhibition of pathological production of CO may confer protection against circulatory collapse. This application proposes experiments in isolated vessel and intact animal preparations to identify the underlying determinants and assess the functional consequences of HO mediated formation of CO in the progression from reversible shock to circulatory collapse after hemorrhagic loss. Accordingly, this information may be developed into strategies in which manipulations of the HO-heme oxygenase-CO system may be applied out of hospital to prevent/reverse hemorrhagic shock, and endogenous CO may serve as an indicator for imminent transition into circulatory collapse.